tbuckley/cabot-search huggingface dataset:
Ambient Air Pollution and Socioeconomic Status in China
Authors: Yuzhou Wang, Yafeng Wang, Hao Xu, Yaohui Zhao, Julian D. Marshall
Journal: Environmental Health Perspectives (2022)

Background: Air pollution disparities by socioeconomic status (SES) are well documented for the United States, with most literature indicating an inverse relationship (i.e., higher concentrations for lower-SES populations). Few studies exist for China, a country accounting for 26% of global premature deaths from ambient air pollution. Objective: Our objective was to test the relationship between ambient air pollution exposures and SES in China. Methods: We combined estimated year 2015 annual-average ambient levels of nitrogen dioxide (NO2) and fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5)] with national demographic information. Pollution estimates were derived from a national empirical model for China at 1-km spatial resolution; demographic estimates were derived from national gridded gross national product (GDP) per capita at 1-km resolution, and (separately) a national representative sample of 21,095 individuals from the China Health and Retirement Longitudinal Study (CHARLS) 2015 cohort. Our use of global data on population density and cohort data on where people live helped avoid the spatial imprecision found in publicly available census data for China. We quantified air pollution disparities among individual’s rural-to-urban migration status; SES factors (education, occupation, and income); and minority status. We compared results using three approaches to SES measurement: individual SES score, community-averaged SES score, and gridded GDP per capita. Results: Ambient NO2 and PM2.5 levels were higher for higher-SES populations than for lower-SES population, higher for long-standing urban residents than for rural-to-urban migrant populations, and higher for the majority ethnic group (Han) than for the average across nine minority groups. For the three SES measurements (individual SES score, community-averaged SES score, gridded GDP per capita), a 1-interquartile range higher SES corresponded to higher concentrations of 6–9 μg/m3 NO2 and 3–6 μg/m3 PM2.5; average concentrations for the highest and lowest 20th percentile of SES differed by 41–89% for NO2 and 12–25% for PM2.5. This pattern held in rural and urban locations, across geographic regions, across a wide range of spatial resolution, and for modeled vs. measured pollution concentrations. Conclusions: Multiple analyses here reveal that in China, ambient NO2 and PM2.5 concentrations are higher for high-SES than for low-SES individuals; these results are robust to multiple sensitivity analyses. Our findings are consistent with the idea that in China’s current industrialization and urbanization stage, economic development is correlated with both SES and air pollution. To our knowledge, our study provides the most comprehensive picture to date of ambient air pollution disparities in China; the results differ dramatically from results and from theories to explain conditions in the United States. https://doi.org/10.1289/EHP9872
Abstract 2581: IL-15 expressing MSCs for NK cell-mediatedcancer immunotherapy
Authors: Drishti Sehgal, No'ad Shanas, Swayam Prabha
Journal: Cancer Research (2022)

Abstract Mesenchymal stem cells (MSCs) offer the possibility of achieving highly selective, tumor-targeted drug delivery because of their ability to home to malignant tissues. IL-15 is currently in clinical trial either alone or as an adjuvant for certain types of metastatic solid tumors. Systemic administration of IL-15 is associated with severe toxicities including hemodynamic imbalance, lymphopenia, and other cytokine-related complications. We hypothesized that tumor targeted delivery of IL-15 using MSCs can improve efficacy and reduce toxicity associated with IL-15. MSCs were engineered to express IL-15 using a lentiviral system (pLenti-C-Myc-DDK-P2A-Puro vector; Invitrogen) tagged with C-terminal MYC/DDK tag for easy detection and purification with anti-DDK antibody. We achieved stable transfection of IL-15 in MSCs (5.7 ng/106 MSCs in 24 hrs; ELISA). Bioactivity of secreted IL-15 was confirmed by splenocyte proliferation assay. We then tested the anticancer activity of IL-15 secreting MSCs in a syngeneic LL/2 lung cancer model. Animals treated with IL-15 secreting MSCs demonstrated significant inhibition of tumor growth and prolonged survival compared to mice treated with IL-15 alone. It was further demonstrated that IL-15 expressing MSCs enhance tumor infiltration of various immune cells. These studies demonstrate the potential of developing novel MSC-based immunotherapy constructs with reduced toxicity. Citation Format: Drishti Sehgal, No'ad Shanas, Swayam Prabha. IL-15 expressing MSCs for NK cell-mediatedcancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2581.
Abstract 6309: Activated neutrophils inhibit chemotactic migration of activated T lymphocytes to CXCL11 by multiple mechanisms
Authors: Kohei Tamura, Yuki Kaneko, Yurie Futoh, Kazuya Takahashi, Yuki Kimura, Akira Saito, Mineyuki Tojo, Hideyo Miyato, Hideyuki Ohzawa, Yasushi Saga, Yuji Takei, Hiroyuki Fujiwara, Joji Kitayama
Journal: Cancer Research (2022)

Abstract Objective High density of tumor-infiltrating lymphocytes (TILs) in the tumor is associated with favorable prognosis of cancer patients, while that of tumor-associated neutrophils (TAN) shows inverse correlation with outcome. We examined the effects of activated neutrophils on chemotactic migration of activated T cells in vitro. Methods Neutrophils and mononuclear cells (PBMC) were collected from the blood of healthy donor. Neutrophils were stimulated with PMA (1uM) or LPS (10ug/ml) for 15 min, washed extensively, and incubated for another 4 hours. PBMC were cultured on anti-CD3 mAb-coated plate with recomnibant-IL-2 (10ng/ml) for 7-14days. The activated T cells were placed in culture inserts with 3μm pore and migration to CXCL-11 (1000ng/ml) placed in lower chamber with or without neutrophils was examined after 2 hours. Random migration of activated T cells on fibronectin coated plate was evaluated with timelapsed analysis using Biostudio system. Degradation of CXCL-11 was examined with western blotting. Results Neutrophils stimulated with PMA or LPS produced neutrophil extracellular traps (NETs). Migration of T cells to CXCL-11 was drastically inhibited in the presence of PMA-activated neutrophils. The inhibition was similarly detected when NETs was removed from PMA-activated neutrophils by ultracentrifugation. Timelapse analysis also showed the NET-depleted supernatant greatly inhibited random migration, which was totally canceled by the pretreatment with 800U/ml catalase. When neutrophils were activated by LPS, T cell migration was also significantly inhibited (p=0.02) but not by NET-depleted supernatant (p=0.99). In western blotting, CXCL11 was totally degraded by LPS-stimulated neutrophils, which was greatly reduced by the depletion of NET component. CXCL11 degraded by NETs was restored by protease inhibitor, 5mM phenylmethylsulfonyl fluoride (PMSF). The reduced migration induced by LPS-stimulated neutrophils was mostly restored with 2mM PMSF. Conclusion Activated neutrophils inhibit chemotactic migration of activated T cells through multiple mechanisms including ROS production and chemokine degradation. TAN may have suppressive effects on the accumulation of TILs. Citation Format: Kohei Tamura, Yuki Kaneko, Yurie Futoh, Kazuya Takahashi, Yuki Kimura, Akira Saito, Mineyuki Tojo, Hideyo Miyato, Hideyuki Ohzawa, Yasushi Saga, Yuji Takei, Hiroyuki Fujiwara, Joji Kitayama. Activated neutrophils inhibit chemotactic migration of activated T lymphocytes to CXCL11 by multiple mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6309.
Abstract 5243: 3-Bromopyruvate in combination with radiation inhibits pancreatic cancer growth by dismantling mitochondria and ATP generation in a preclinical mouse model
Authors: Sanjit K. Roy, Tijana Dukic, Binny Bhandary, Aneesh Acharya, Kevin J. Tu, Young H. Ko, Hem D. Shukla
Journal: Cancer Research (2022)

Abstract 3-Bromopyruvate (3 BP) is a promising anticancer drug against pancreatic cancer. It exerts potent anticancer effects by inhibiting hexokinase II enzyme of glycolysis pathway and ATP generation in cancer cells. In present investigation we have examined the effect of 3-BromoPyruvate employing panc-2 cancer cells, and syngeneic pancreatic cancer mouse model. The clonogenic survival assay demonstrated dose dependent inhibition of cell growth, and we observed 95% cell death at 15 uM conc. Further, ATP production was severely inhibited in cancer cells treated with same concentration of 3-BP. We also observed that 3-BP in combination with low doses of irradiation was more effective in killing cancer cells than 3-BP alone. Electron microscopy revealed that 3-BromoPyruvate severely damaged mitochondrial integrity which might have severely affected ATP generation in cancer cells. We further tested 3-BromoPyruvate (2.5-10.0 mg/kg) in syngeneic panc-2 tumor mouse model and observed that 3-BP at10.0 mg/kg dose significantly reduced tumor growth (volume) about 35-40%. Immunohistochemistry (IHC) data showed that 3-BP inhibits hexokinase II (HK2) and TGFbeta1 and enhanced active caspase-3 expression in tumor tissues as compared to untreated control. The disruption of the interaction between VDAC1 and HK2 due to 3BP treatment was confirmed by CO-IP. Interestingly, 3 BP at higher dose induces caspase-3 activation in tumor derived organoid without showing any effect on normal pancreatic organoid. Altogether, the results in this study demonstrated that 3 BP could be a promising anti-tumor drug against pancreatic cancer and its efficacy could be improved in combination with radiation therapy. Citation Format: Sanjit K. Roy, Tijana Dukic, Binny Bhandary, Aneesh Acharya, Kevin J. Tu, Young H. Ko, Hem D. Shukla. 3-Bromopyruvate in combination with radiation inhibits pancreatic cancer growth by dismantling mitochondria and ATP generation in a preclinical mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5243.
Surgical Decision-making in Early-Stage Breast Cancer—Trends and Opportunities
Authors: Laura S. Dominici, Tari A. King
Journal: JAMA Surgery (2022)

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Abstract 1344: Immune transcriptional profiling in a large animal model of histiocytic sarcoma reveals putative drivers and tumor suppressors
Authors: Jennifer A. Lenz, Charles-Antoine Assenmacher, Enrico Radaelli, Matthew J. Atherton
Journal: Cancer Research (2022)

Abstract Histiocytic sarcoma (HS) is a rare, yet lethal malignancy with a median overall survival of six months and no universally agreed standard of care therapy. Due to the paucity of human cases, there is a drive to develop model systems to improve our understanding of the pathology underlying this disease and screen new treatment strategies. Spontaneous canine HS exhibits increased prevalence in specific breeds, shares key genetic and biologic similarities with the human disease, and occurs in an immunocompetent setting. Our previous studies revealed a spectrum of hot and cold immune tumor microenvironments (TME) based on tumor infiltrating lymphocyte (TIL) quantification in 18 canine and 5 human HS cases. In dogs, increased TIL densities were positively associated with longer survival times. Despite this association, the disease course of HS in our veterinary patient cohort was nearly uniformly fatal. To evaluate for potential inhibitors of T cell immunity in the TME and identify putative drivers and suppressors of HS, we performed immune transcription profiling. Tumors were selected from 3 short-lived cases of splenic HS that were sparsely infiltrated with TIL and 3 long-lived cases of pulmonary HS that were T cell inflamed. Tumors were compared to corresponding grossly healthy splenic and lung tissues collected from 3 dogs without neoplasia undergoing routine post-mortem examination. RNA was extracted from formalin-fixed paraffin embedded tissues and immune transcription profiling was performed using the NanoString nCounter Canine IO Panel. Analyses of all tumors compared to normal tissues, and subset analyses of tissues stratified based on tissue origin site, revealed enrichment of ITGAX (CD11c) expression in the HS tumor samples consistent with histiocytic origin. In each subset analysis, SPP1 (osteopontin) was highly expressed in HS tumors compared with normal tissues. Osteopontin has been shown to be protumorigenic in a variety of cancers, is a potent chemokine for macrophages, and can suppress T cell activation through ligation of CD44, thus acting as a T cell checkpoint. Additionally, we found decreased expression of TXNIP in HS tumors compared to healthy tissues. TXNIP is an established tumor suppressor gene in various tumor types, including acute myeloid leukemia. Future studies will interrogate the functional implications of these transcriptional changes with the aim of developing novel therapeutic strategies for HS in both species. Citation Format: Jennifer A. Lenz, Charles-Antoine Assenmacher, Enrico Radaelli, Matthew J. Atherton. Immune transcriptional profiling in a large animal model of histiocytic sarcoma reveals putative drivers and tumor suppressors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1344.
Abstract 817: microRNA-26a-5p is a prognostic factor that regulates cancer stemness
Authors: Daeun Kang, Chang Ryul Park, Minhyeok Lee, Su Yel Lee, Se Jin Park, Wan Jin Hwang, Gwan Woo Ku, Seong Lan Yu, In Beom Jeong, Sun Jung Kwon, Jaeku Kang, Eung Bae Lee, Ji Woong Son
Journal: Cancer Research (2022)

Abstract Background: Cancer stem cells (CSCs) identified in lung cancer exhibit resistance to chemotherapy, radiotherapy, and targeted therapy. Therefore, a technology to control of CSCs is needed to overcome such resistance to cancer therapy. Various evidences about the association between epithelial-mesenchymal transition related transcriptomic alteration and acquisition of CSC phenotype have been proposed recently. In our previous research, down-regulated miR-26a-5p is closely related to mesenchymal-like lung cancer cell lines. These findings suggest that miR-26a-5p might be involved in lung cancer stemness. Methods: RNA polymerase III subunit G (POLR3G) was selected as a candidate target of miR-26a-5p related to cancer stemness. its quantitative relationship was investigated by polymerase chain reaction, western blot after transfection of miR-26a-5p. luciferase assay were done for investigating the direct regulation of miR-26a-5p on POLR3G expression. After transfection of miR-26a-5p, colony formation assay and sphere formation assay were performed to evaluate the effect on cancer stemness. By treating cancer cell by miR-26a-5p and paclitaxel, cell viability was checked by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and Muse cell analyzer. Expression level of each gene and its impact on survival were revealed by the cancer genome atlas pancancer database. Results: miR-26a-5p regulated the expression of POLR3G directly. Overexpression of miR-26a-5p induced down regulation of POLR3G and a marked reduction of colony formation and sphere formation. Co-treatment of miR-26a-5p with paclitaxel decreased cell growth, suggesting that miR-26a-5p might play a role as a chemotherapy sensitizer. In the cancer genome atlas data, down-regulated miR-26a-5p and up-regulated POLR3G were shown compared to adjacent normal tissue. High miR-26a-5p and low POLR3G expression were also related to higher survival rate of patients with lung adenocarcinoma. Conclusions: Overexpression of miR-26a-5p can suppress lung cancer stemness and make cancer cell become sensitive to chemotherapy. This finding provides a novel insight into a potential lung cancer treatment by regulating stemness. Citation Format: Daeun Kang, Chang Ryul Park, Minhyeok Lee, Su Yel Lee, Se Jin Park, Wan Jin Hwang, Gwan Woo Ku, Seong Lan Yu, In Beom Jeong, Sun Jung Kwon, Jaeku Kang, Eung Bae Lee, Ji Woong Son. microRNA-26a-5p is a prognostic factor that regulates cancer stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 817.
DNA methylation signatures reveal that distinct combinations of transcription factors specify human immune cell epigenetic identity
Authors: Roshni Roy, Senthilkumar Ramamoorthy, Benjamin D. Shapiro, Mary Kaileh, Dena Hernandez, Dimitra Sarantopoulou, Sampath Arepalli, Sö ren Boller, Amit Singh, Arsun Bektas, Jaekwan Kim, Ann Zenobia Moore, Toshiko Tanaka, Julia McKelvey, Linda Zukley, Cuong Nguyen, Tonya Wallace, Christopher Dunn, Robert Wersto, William Wood, Yulan Piao, Kevin G. Becker, Christopher Coletta, Supriyo De, Jyoti Misra Sen, Alexis Battle, Nan-ping Weng, Rudolf Grosschedl, Luigi Ferrucci, Ranjan Sen
Journal: Immunity (2022)
Abstract 819: ERBB4 mediates IL10-induced growth of EGFR-independent colon tumors
Authors: Michael P. McGill, Carolina Mantilla Rojas, David W. Threadgill
Journal: Cancer Research (2022)

Abstract ERBB4 is commonly over-expressed in human CRC, however the utility of ERBB4 as a target for colorectal cancer (CRC) therapeutics is largely unexplored. Our group recently identified a molecular subtype of CRC that arises independent of EGFR and displays a more aggressive growth phenotype than those dependent on EGFR. The robust growth phenotype of EGFR-independent tumors can be in part attributed to upregulation of IL10 signaling. In addition, EGFR-independent tumors display a significant upregulation of Erbb2 and Erbb4 transcripts in both spontaneous and sporadic CRC mouse models, perhaps compensating for the loss of EGFR. To investigate the importance of other ERBB receptors in EGFR-independent CRC tumor progression, we ablated Erbb4 to interrogate its influence on tumor development in vivo using a conditional allele of Erbb4tm1Fej (Erbb4f). ERBB4-deficient ApcMin/+ mice (ApcMin/+, ErbB4f/f, Tg(Vil1-Cre)) were established and used to show that ERBB4 ablation in the intestinal epithelia results in a significant decrease in the number of intestinal and colon tumors. Polyps lacking ERBB4 were also significantly reduced size, contrary to what is observed with loss of EGFR. We also recently developed ERBB2-deficient ApcMin/+ mice, and preliminary results suggest that Erbb2 ablation also results in a decrease in intestinal and colon tumor number and size. Consistent with data from EGFR-independent tumors, transcriptomic analysis of ERBB4-deficient intestinal tumors predicted down-regulation of IL10 signaling, which was validated through Il10 and Socs3 qPCR. To complement our findings, the observed down-regulation of Il10 and Socs3 at the transcript level corresponded with a significant decrease in IL10 levels in the serum of mice harboring ERBB4 deficient tumors when compared to mice without tumors. Furthermore, we found that transcript levels of Erbb4 significantly decreased after anti-IL10 treatment of EGFR-independent tumors in vivo. This illustrates a possible negative feedback loop whereby neutralizing IL10 also leads to a reduction of Erbb4 expression, further reducing IL10 signaling. Taken together, the data suggest that the absence of EGFR triggers Erbb4 upregulation, implicating an important role for ERBB4 in EGFR-independent colon tumor growth. These results suggest that therapeutic targeting of ERBB4 may lead to a reduction in IL10 signaling and reduced intestinal polyp multiplicity and size in EGFR-independent tumors and inform the development of novel approaches to treat CRC that exhibit aberrant expression of EGFR and ERBB4. Citation Format: Michael P. McGill, Carolina Mantilla Rojas, David W. Threadgill. ERBB4 mediates IL10-induced growth of EGFR-independent colon tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 819.
Abstract 5670: TRPM8 ion channel role in prostate cancer: Actions as a rapid testosterone signaling receptor
Authors: Kiran Velpula, Katherine Shishido, Susovon Bayen, Swapna Asuthkar
Journal: Cancer Research (2022)

Abstract The transient receptor potential melastatin 8 (TRPM8) is well-known for its role in cold sensation in somatosensory neurons. TRPM8 was first identified as a prostate epithelial cell-specific gene, however, its role was unclear due to the absence of its endogenous agonist. We are the first to discover the novel role of TRPM8 as a rapid testosterone receptor. The TRPM8 mRNA is highly expressed in prostate cancer (PC) and is lost during the transition to androgen-independent prostate cancer (AIPC). Although emerging studies have shed light regarding androgen regulation of TRPM8 mRNA expression, we found that the addition of androgen receptor (AR) on the lipid bilayers inhibited testosterone-TRPM8 induced Ca2+ uptake. Additionally, our IHC revealed increased internalization of the TRPM8 protein in high-grade PC and that TRPM8 protein was targeted for proteasomal degradation in PC. We observed that inhibition of AR and UBA1 promoted the stabilization of TRPM8 on the plasma membrane, triggering Ca2+-induced cytotoxicity and apoptosis in both androgen dependent and androgen independent PC cells. Furthermore, in line with previous studies, we showed that testosterone-induced TRPM8 activation on the planar lipid bilayers also required phosphatidylinositol 4,5-bisphosphate (PIP2). Loss of PTEN is associated with tumor recurrence and the transition to AIPC. Thus, PTEN loss mediated PIP2 deficiency may be an important mechanism of TRPM8 desensitization in PC. Therefore, we propose that the rescue of TRPM8 activity on the plasma membrane combined with AR targeting may be an effective therapy for PC. Citation Format: Kiran Velpula, Katherine Shishido, Susovon Bayen, Swapna Asuthkar. TRPM8 ion channel role in prostate cancer: Actions as a rapid testosterone signaling receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5670.